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Acta Neuropathol Commun. 2018 Jul 26;6(1):67. doi: 10.1186/s40478-018-0570-9.

Medulloblastoma therapy generates risk of a poorly-prognostic H3 wild-type subgroup of diffuse intrinsic pontine glioma: a report from the International DIPG Registry.

Author information

1
Department of Pediatrics, Division of Pediatric Hematology-Oncology; Michigan Medicine, Ann Arbor, MI, 48109, USA.
2
Department of Pathology, Michigan Medicine, Ann Arbor, MI, 48109, USA.
3
Department of Haematology and Oncology, Princess Margaret Hospital for Children, Perth, WA, 6840, Australia.
4
Michigan Center for Translational Pathology, Michigan Medicine, Ann Arbor, MI, 48109, USA.
5
Ontario Institute for Cancer Research, MG5 0A3, Toronto, ON, Canada.
6
Department of Radiation Oncology; Michigan Medicine, Ann Arbor, MI, 48109, USA.
7
Department of Computational Medicine and Bioinformatics; Michigan Medicine, Ann Arbor, MI, 48109, USA.
8
Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, 48109, USA.
9
Division of Radiology, Cincinnati Children's Hospital, Cincinnati, OH, 45229, USA.
10
Division of Oncology, Cincinnati Children's Hospital, Cincinnati, OH, 45229, USA.
11
Division of Biomedical Informatics, Cincinnati Children's Hospital, Cincinnati, OH, 45229, USA.
12
Division of Pathology, Cincinnati Children's Hospital, Cincinnati, OH, 45229, USA.
13
Department of Pediatrics, Division of Oncology, Seattle Children's Hospital, Seattle, WA, 98105, USA.
14
Department of Pediatrics, Division of Haematology/Oncology, Hospital for Sick Children, Toronto, ON, M5G 1X8, Canada.
15
Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, 02114, USA.
16
Department of Pediatrics, Division of Neurology; Michigan Medicine, Ann Arbor, MI, 48109, USA.
17
Department of Pediatrics, Division of Oncology, Cincinnati Children's Hospital, Cincinnati, OH, 45229, USA.
18
Kids Cancer Centre, Telethon Kids Institute, Subiaco, WA, 6008, Australia.
19
Division of Paediatrics, University of Western Australia, Crawley, WA, 6009, Australia.
20
Department of Pediatrics, Division of Pediatric Hematology-Oncology; Michigan Medicine, Ann Arbor, MI, 48109, USA. ckoschma@med.umich.edu.

Abstract

With improved survivorship in medulloblastoma, there has been an increasing incidence of late complications. To date, no studies have specifically addressed the risk of radiation-associated diffuse intrinsic pontine glioma (DIPG) in medulloblastoma survivors. Query of the International DIPG Registry identified six cases of DIPG with a history of medulloblastoma treated with radiotherapy. All patients underwent central radiologic review that confirmed a diagnosis of DIPG. Six additional cases were identified in reports from recent cooperative group medulloblastoma trials (total n = 12; ages 7 to 21 years). From these cases, molecular subgrouping of primary medulloblastomas with available tissue (n = 5) revealed only non-WNT, non-SHH subgroups (group 3 or 4). The estimated cumulative incidence of DIPG after post-treatment medulloblastoma ranged from 0.3-3.9%. Posterior fossa radiation exposure (including brainstem) was greater than 53.0 Gy in all cases with available details. Tumor/germline exome sequencing of three radiation-associated DIPGs revealed an H3 wild-type status and mutational signature distinct from primary DIPG with evidence of radiation-induced DNA damage. Mutations identified in the radiation-associated DIPGs had significant molecular overlap with recurrent drivers of adult glioblastoma (e.g. NRAS, EGFR, and PTEN), as opposed to epigenetic dysregulation in H3-driven primary DIPGs. Patients with radiation-associated DIPG had a significantly worse median overall survival (median 8 months; range 4-17 months) compared to patients with primary DIPG. Here, it is demonstrated that DIPG occurs as a not infrequent complication of radiation therapy in survivors of pediatric medulloblastoma and that radiation-associated DIPGs may present as a poorly-prognostic distinct molecular subgroup of H3 wild-type DIPG. Given the abysmal survival of these cases, these findings provide a compelling argument for efforts to reduce exposure of the brainstem in the treatment of medulloblastoma. Additionally, patients with radiation-associated DIPG may benefit from future therapies targeted to the molecular features of adult glioblastoma rather than primary DIPG.

KEYWORDS:

Brainstem; Cranial irradiation; Diffuse intrinsic pontine glioma; Medulloblastoma; Secondary malignant neoplasm

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